RELEVANCE Studies in human subjects and animal models indicate gender-specific differences in Se utilization and metabolism. Selenium supplementation at high levels in a clinical study resulted in increased risk for development of type 2 diabetes in men but not in women, and our results indicate gender-specific differences in Se handling in animals. These findings have crucial implications for the use of Se supplements in human health and disease, and highlight the importance of investigating the mechanistic basis for these gender- specific differences.